The present invention relates in general to the field of α-haloenamine chemistry, processes for the preparation of α-haloenamines and, in one embodiment, to α-haloenamine reagents supported by an organic or inorganic material which, under a defined set of conditions, renders the supported reagent sufficiently insoluble to enable separation of the reagent from a mixture.
α-Haloenamine reagents are used in a number of synthetic reactions. For example, they are used to convert carboxylic acids to acid halides, alcohols to halides, sugars to sugar halides, and thiophosphoryl compounds to the corresponding phosphoryl halides. α-haloenamine reagents offer advantages over other reagents for such conversions, particularly under neutral conditions and in those instances in which the substrate for the reaction contains one or more sensitive functionalities.
Despite these advantages, haloenamines are not being used to their full potential for a variety of reasons. Among these reasons are synthetic challenges. Ghosez et al. (Angew. Chem. Int. Ed. Engl. 1969, 8, 454) disclosed a route which involved the reaction of tertiary amides with phosgene followed by the dehydrochlorination of the intermediate α-chloroiminium salts with triethylamine. According to Ghosez et al., the hazard associated with the use of large amounts of phosgene as well as the ban on phosgene in many laboratories led them to re-examine the preparation of β-disubstituted-α-chloroenamines; more recently, Ghosez et al. (Tetrahedron 54 (1998) 9207-9222) reported a synthetic route which was said to be conceptually the same as the previous one: it involved the reaction of a tertiary amide with a chlorinating agent followed by the elimination of hydrochloric acid from the resulting α-chloroiminium salt. The halogenating agents tried by Ghosez et al. were thionyl chloride, diphosgene, triphosgene, phosphorous oxychloride, and phosphorous oxybromide. Of these, only phosphorous oxychloride was said to be suitable for the preparation of large amounts of α-chloroenamines. Thionyl chloride was said to be unsuitable. Diphosgene and triphosgene were said to be suitable although in both cases aminor by-product was produced. As a result, Ghosez et al. stated that phosphorous oxychloride would probably supersede phosgene as the halogenating agent. Ghosez et al. also reported that they succeeded in preparing the corresponding α-bromoenamines which, until then, they said were only available by halide exchange. Despite the advances reported by Ghosez et al., the conversion of a tertiary amide to an α-chloroiminium salt, particularly when the nitrogen substituents are bulky can be difficult.
Recent advances in molecular biology, chemistry and automation have resulted in the development of rapid, high throughput screening (HTS) protocols to synthesize and screen large numbers of compounds for a desired activity or other desirable property in parallel. These advances have been facilitated by fundamental developments in chemistry, including the development of highly sensitive analytical methods, solid state chemical synthesis, and sensitive and specific biological assay systems. As a result, it is now common to carry out such reactions, in parallel, in a multi-well micro titer plate or other substratum having a plurality of wells for containing a reaction mixture, e.g., 96, 384 or even a greater number of wells. To date, however, α-haloenamine reagents have not been provided in a form which would enable rapid, automated use and purification from such reaction mixtures.